The frequency and temporal patterns of adverse effects of antipneumocystis therapy were assessed in a multicenter trial comparing atovaquone to trimethoprim-sulfa for therapy of AIDS related pneumocystis pneumonia Adverse reactions to TMP-SMX occurred primarily after the first seven days of therapy, cytopenias, and nephritis were dose related. Adverse effects of atovaquone were unusual. This study suggests than an optimal regimen for therapy of pneumocystis pneumonia might be combination therapy with only seven days of TMP-SMX given at doses less than currently recommended, in combination with 21 days of atovaquone. This strategy would avoid most toxicities due to TMP-SMX, which occur often the seventh day, and would allow prompt antipneumocystis effect not easily achieved by atovaquone due to the long interval needed to attain steady state levels.